This invention relates to a time-of-flight mass spectrometer and its associated ion detection system. It provides apparatus for detecting ions in a time-of-flight mass spectrometer, and methods of operating that apparatus, which result in improved performance at a lower cost when compared with prior spectrometers.
In a time-of-flight mass spectrometer, a bunch of ions enters a field-free drift region with the same kinetic energy and the ions temporally separate according to their mass-to-charge ratios because they travel with different velocities. Ions having different mass-to-charge ratios therefore arrive at a detector disposed at the distal end of the drift region at different times, and their mass-to-charge ratios are determined by measurement of their transit time through the drift region.
Prior detectors for time-of-flight mass spectrometers comprise an ion-electron converter followed by an electron multiplying device. In some embodiments, ions strike a surface of the multiplying device to release electrons and a separate converter is not provided. Because the detector must respond to ions leaving the whole exit aperture of the drift region, it is conventional to use one or more microchannel plate electron multipliers as the multiplying device. A collector electrode is disposed to receive the electrons produced by the microchannel plates and means are provided to respond to the current flow so generated and produce an output signal. The chief difference between such a detector and the similar device conventionally used with magnetic sector, quadrupole or quadrupole ion-trap spectrometers is the electronic signal processing, which must produce signals indicative of the transit time of the ions as well as the number arriving in any particular time window (corresponding to one or more mass-to-charge ratios). This data must be generated and read out before the next bunch of ions can be admitted into the drift region, so that detector speed is an important determinant of the repetition rate, and hence the sensitivity, of the entire spectrometer.
The earliest detectors for time-of-flight spectrometers comprised a DC amplifier connected to the collector electrode and an analogue-to-digital converter (ADC) for digitizing the output of the amplifier. Usually, this arrangement was used with time-slice detection whereby the amplifier was gated to respond only to ions arriving within a certain time window (typically corresponding to one mass unit). The time window was moved (relative to the time of entrance of ions into the drift region) during repeated cycles of operation so that a complete mass spectrum was eventually recorded. An improvement involved the use of several amplifiers and ADC""s arranged to simultaneously record a different time window. Nevertheless, many cycles of the spectrometer are still required to record a complete mass spectrum and the repetition rate of the spectrometer is severely limited by the time taken for the analogue-digital conversion in each cycle. Digital transient recorders (for example, as described in U.S. Pat. Nos. 4,490,806, 5,428,357 and PCT applications WO94/28631 and WO95/00236) have been devised to efficiently process the digital data produced by the ADC, but, particularly in the case of time-of-flight mass analyzers for the analysis of ions from continuous (as opposed to pulsed) ion sources, these do not represent a cost-effective solution to the problem of achieving a high repetition rate.
An alternative detection system for time-of-flight mass spectrometers is based on ion counting. In these methods, a signal due to a single ion impact on the detector is converted to a digital boolean value, xe2x80x9ctruexe2x80x9d (which may be represented by a digital xe2x80x9c1xe2x80x9d) in the case of an ion impact, or xe2x80x9cfalsexe2x80x9d (e.g, a digital xe2x80x9c0xe2x80x9d) if there has been no ion impact. Various types of timers and/or counters are then employed to process the digital data produced. For example, a counter associated with a particular time window may be incremented whenever a signal is generated in that time window. Alternatively, the output of a timer, started when an ion bunch enters, may be stored in a memory array whenever the detector generates a xe2x80x9ctruexe2x80x9d signal. The advantage of an ion-counting detector over an analogue detector is that variations in the output signal of the electron multiplier due to a single ion impact, which may be xc2x150% or more, are effectively eliminated because each signal above the noise threshold is treated identically. Further, an ion counting detector does not suffer from the additional noise inevitably produced by the ADC incorporated in an analogue detector system, and is also faster in operation. Consequently, the contribution of noise to the overall ion count is reduced and a more accurate ion count is achieved, particularly in the case of small numbers of ions. The disadvantage is that the digital signal representing an ion impact must be processed very quickly, before the next ion arrives at the detector, if that ion is to be detected. In practice, all detectors have a deadtime immediately following an ion impact, during which they cannot respond to an ion impact. This limits the number of ions which can be detected in a given time, so that a dynamic range of the detector is also limited. Corrections can be made to the detector output to compensate for the effects of deadtime (see, for example, Stephen, Zehnpfenning and Benninghoven, J. Vac. Sci. Technol. A, 1994 vol 12 (2) pp 405-410), and in corresponding EP patent application claiming priority solely from GB 9801565.4 filed Jan. 23, 1998 (Agents Ref: 80.85.67750/004), but even when such corrections are carried out the detector dynamic range still effectively reduces the performance of a time-of-flight mass spectrometer with such a detector.
An improved ion-counting detector for time-of-flight mass spectrometry has been described in general terms by Rockwood at the 1997 Pittsburgh Conference, Atlanta, Ga. (paper No 733), and is available commercially from Sensar Larsen-Davis as the xe2x80x9cSimulpulsexe2x80x9d detector. According to information published by Sensar Larson-Davis it comprises a large number of individual equal-area anodes, each of which is provided with a digital pulse generating circuit which is triggered by the arrival of an ion at its associated anode. The anodes are disposed in a wide-area detector so that they are all equally likely to be struck by an ion exiting from the drift region. Consequently, simultaneous (or near-simultaneous) ion strikes are most likely to occur on different electrodes and the effect of detector deadtime is greatly reduced. The data from each of the anodes is summed into an 8-bit digital word representative of the ion intensity at any particular time, and the value of that word and its associated time is stored in a digital memory. However, such a detector is obviously complicated and expensive to manufacture.
An electron multiplier ion detector for a scanning mass spectrometer which has two modes of operation to extend its dynamic range is disclosed by Kristo and Enke in Rev. Sci. Instrum. 1988 vol 59 (3) pp 438-442. This detector comprises two channel type electron multipliers in series together with an intermediate anode. The intermediate anode was arranged to intercept approximately 90% of the electrons leaving the first multiplier and to allow the remainder to enter the second multiplier. An analogue amplifier was connected to the intermediate anode and a discriminator and pulse counter connected to an electrode disposed to receive electrons leaving the second multiplier. The outputs of the analogue amplifier and pulse counter were electronically combined. A protection grid was also disposed between the multipliers. At high incident ion fluxes, the output signal comprised the output of the analogue amplifier connected to the intermediate anode. Under these conditions a potential was applied to the protection grid to prevent electrons entering the second multiplier (which might otherwise cause damage to the second multiplier). At low ion fluxes, the potential on the protecting grid was turned off and the output signal comprised the output of the pulse counter. In this mode the detector operated in the single ion counting mode. In this way the detector was operable in a low sensitivity analogue mode using the intermediate anode and a high sensitivity ion counting mode using both multipliers and the pulse counter, so that the dynamic range was considerably greater than a conventional detector which use only one of these modes.
Other prior art teaching of electron multipliers with means for extending the dynamic range includes a simultaneous mode (i.e., pulse counting and analogue) electron multiplier taught in U.S. Pat. No. 5,463,219. U.S. Pat. No. 4,691,160 teaches a discrete dynode electron multiplier having two final collector electrodes of different areas, each connected to a separate analogue amplifier and selectable by means of a manually operated switch. Soviet Inventors Certificate SU 851549 teaches the disposition of a control grid between two channelplate electron multipliers, the potential on which can be adjusted to control the gain of the assembly. GB patent application 2300513 A teaches a similar control grid disposed between certain dynode sheets in an electron multiplier comprising a stack of such sheets, and which is especially suitable for a photomultiplier tube. Prior art disclosed in U.S. Pat. No. 4,691,160 also comprises a continuous dynode electron multiplier having two collector electrodes, one of which is capable of receiving electrons from a dynode disposed prior to the final dynode so that the multiplier has less gain.
Co-pending PCT patent application claiming priority from GB9801565.4, GB9804286.4, GB9810867.3 and GB9813224.4 and filed simultaneously herewith (Agents Ref: 80.85.67901/003) teaches a time-of-flight mass spectrometer having an ion-counting channelplate detector with two or more collection electrodes of unequal areas and means for automatically selecting data from the most appropriate electrode according to the ion flux at different mass to charge ratios. In this way the dynamic range of the detector is extended by switching to data from a smaller electrode whenever the data from a larger electrode is likely to be inaccurate due to detector deadtime.
It is an object of the present invention to provide a time-of-flight mass spectrometer and a detector therefor, which has a greater dynamic range than most prior apparatus and which is cheaper to manufacture than prior spectrometers and detectors of equivalent performance. It is a further object to provide methods for operating such a spectrometer and detector.
According to a first aspect of the present invention there is provided a time-of-flight mass spectrometer.
In a preferred embodiment a second electron multiplying means may be provided between the first collection electrode and the second collection electrode to receive electrons which are not collected on the first collection electrode and to generate a greater number of electrons per ion entering the detector at the second collection electrode than at the first collection electrode.
Alternatively, both collection electrodes can be disposed to receive secondary electrons from a single electron multiplying means but the first electrode may have a smaller effective area than the second collection electrode so that the second collection electrode receives more electrons per ion entering the detector.
The term xe2x80x9ceffective areaxe2x80x9d means that area of a collection electrode which actually receives the secondary electrons. Thus the first collection electrode may comprise a grid-like electrode of smaller effective area than the second collection electrode.
In an alternative embodiment, the grid-like electrode(s) may be replaced with at least one, preferably a single, wire electrode.
The signal processing means associated with each of the collection electrodes may comprise an analogue or a digital (i.e, pulse-counting) system. Preferably, both signal processing means are digital, but in a less preferred embodiment one may be digital and the other may be analogue.
Analogue signal processing means may comprise a fast analogue amplifier followed by an A-D converter which outputs a digital signal to the memory means on receipt of a clock pulse.
Pulse-counting signal processing means may comprise a discriminator which generates a digital xe2x80x9ctruexe2x80x9d signal to the memory means in response to the arrival of secondary electrons at the collection electrode in the period immediately preceding a clock pulse.
Typically, a digital signal processing means is used in association with the second collection electrode to provide the maximum sensitivity. A pulse-counting system of this nature unavoidably suffers from dead-time errors such that immediately following triggering of the discriminator the discriminator is unable to respond for a time, and co-pending PCT patent application claiming priority from GB9801565.4, GB9804286.4, GB9810867.3 and GB9813224.4 and filed simultaneously herewith (Agents Ref: 80.85.67901/003) teaches apparatus and methods for minimizing this problem in a similar detector system for a time-of-flight mass spectrometer.
Preferred embodiment of the memory means of the invention may comprise RAM associated with a suitably programmed digital computer or microprocessor. Thus, a spectrometer cycle is started each time a bunch of ions enters the drift region. In the case of an analogue signal processing means, a clock generator may cause the signal processing means to store the digital output of signal processing means in the memory means at a series of transit times corresponding to the ticks of the clock generator during that spectrometer cycle.
After all the ions of interest have travelled through the drift region the spectrometer cycle is terminated, a new bunch of ions is generated and a new cycle is started. Data at each clock tick from this and subsequent cycles may then be added to the data previously stored in the memory means for the same transit time value.
In the case of a pulse-counting detector a similar arrangement may be adopted, storing for example, a digital xe2x80x9c1xe2x80x9d at the clock tick immediately following the triggering of the fast discriminator by an ion arrival at the associated collection electrode and accumulating valves at corresponding transit times in subsequent detector cycles. Alternatively, memory may be conserved by storing only each transit time at which an ion triggers the fast discriminator.
In accordance with the preferred embodiment of the invention the output means is operative to determine the quantity of ions entering the detector at one or more transit times subsequent to the completion of at least one, and more usually many, spectrometer cycles.
The number of cycles during which acquisition takes place will be dependent on the rate at which the mass spectrum is changing and the capacity of the memory means. For example, in the case of a TOF spectrometer used for monitoring fast chromatographic peaks the repetition rate may be 10 kHz and data may be stored for about 0.5 seconds (ie, approximately 5,000 spectrometer cycles) in the memory means before being processed by the output means. Longer time periods and lower repetition rates are more typical for MALDI TOF spectrometers.
Once the data from the desired number of spectrometer cycles has been acquired, the output means may generate mass spectral data in the form of the quantity of ions entering the detector at each of one or more transit times.
The output means preferably uses the data associated with the second collection electrode (or the data associated with both the first and second collection electrodes) in order to obtain the maximum sensitivity.
However, data associated with the second electrode may be unreliable at certain transit times if the number of ions entering the detector at a particular transit time exceeds a certain limit, for example because of detector dead-time in the case of pulse-counting signal processing means or because of saturation of the A-D converter in an analogue signal processing means. In such circumstances the output means may use data from the first collection electrode alone, which data is less likely to suffer from deadtime or saturation problems.
Conveniently, a decision on whether data from the second collection electrode is reliable at any given transit time is made from an examination of the data from the first collection electrode which has been stored in the memory means at the relevant transit time. The relative gains of the detector system of the collection electrodes and their associated signal processing means is known (either by experimental calibration or from the ratio of the areas of different sized collection electrodes) so that a threshold output level may be set in relation to the output of the signal processing means associated with the first collection electrode above which data associated with the second collection electrode should not be used.
Preferably the output means comprises a suitably programmed digital computer.
According to a second aspect of the present invention there is provided a method of time-of-flight mass spectrometry.
It will be appreciated that according to the invention and in contrast to the prior art of U.S. Pat. No. 5,463,219 it is not necessary to provide fast hardware to examine the signals generated by the first collection electrode while the data is being acquired. Instead, the decision as to whether data associated with the second collection electrode is valid is made once all the data from a plurality of ion bunches has been stored in the memory means. Consequently the speed at which data from the collection electrodes can be stored in the memory means is increased. This is especially important in the case of a time-of-flight spectrometer if the rate of generation of ion bunches, and hence the sensitivity of the spectrometer, is not to be degraded. Prior types of dual mode electron multipliers (e.g, that described in U.S. Pat. No. 5,463,219) intended for scanning mass spectrometers require hardware for monitoring the low-gain output signal in order to activate some means of preventing damage to the high-gain section of the multiplier when the ion beam flux exceeds a certain value. However, with a time-of-flight spectrometer this situation does not arise so readily because the number of ions arriving in each bunch will generally be far less than the number likely to cause damage to the multiplier. These prior types of dual-made multipliers are unsuited to use with a time-of-flight mass spectrometer because the presence of the protection system reduces the rate of data acquisition. The present inventors have realized that the limitation on dynamic range in the case of a time-of-flight detector is more likely to be imposed by the limited dynamic range of a sufficiently fast A-D converter, or the dead-time of a pulse-counting system, and not by the possibility of saturation of or damage to the multiplier itself. Thus, the present invention overcomes the limitations of prior dual-mode detectors when used for time-of-flight mass spectroscopy by storing data from the collection electrodes directly in the memory means and requiring no additional real-time processing or slow electronic hardware, and therefore, provides a detector with extended dynamic range which does not require the repetition rate of the spectrometer to be reduced.
Preferred variations on the method will be apparent from the discussion presented above in respect of the apparatus of the invention.